The overall goal of this project is to define the interplay between inflammation, oxidative stress, fibrosis and atrial fibrillation by addressing the hypothesis that fish oil reduces the recurrence of atrial fibrillation, and does so through anti-inflammatory, antifibrotic and antioxidant mechanisms. Atrial fibrillation is the most common serious arrhythmia - it affects approximately 2% of the population and doubles mortality. The incidence of atrial fibrillation is increasing, and treatment is only modestly effective. Recent in vitro and clinical studies suggest that inflammation plays a fundamental role in the pathogenesis of atrial fibrillation. Inflammation, and the resulting oxidative stress, alter electrical and structural remodeling, thus promoting both the onset and recurrence of atrial fibrillation. Markers of inflammation such as C-reactive protein (CRP) and interleukin-6 (IL-6) are elevated in patients with atrial fibrillation. Furthermore, fish oil, an intervention known to have anti-inflammatory, antifibrotic and antioxidant effects, markedly reduced postoperative atrial fibrillation. The mechanisms through which fish oil may exert benefits in atrial fibrillation are not known, nor is it known if the beneficial effects observed in postoperative atrial fibrillation extend to the much more common type of fibrillation present in the general population. Accordingly, in Specific Aim 1 we will test the hypothesis that supplementary fish oil reduces the risk of recurrence of atrial fibrillation in a randomized, double-blind, placebo-controlled study. Specific Aim 2 will address the hypothesis that fish oil has anti-inflammatory, anti- fibrotic and antioxidant effects and reduces the risk of recurrence of atrial fibrillation through these mechanisms. The recently demonstrated efficacy of fish oil in the prevention of postoperative atrial fibrillation, the wealth of scientific information showing that it has antiarrhythmic effects, and its excellent safety profile all indicate that the assessment of its efficacy in the maintenance of sinus rhythm in patients with atrial fibrillation is a high priority. The mechanistic approach that underlies the proposed studies will not only provide answers to the question of clinical efficacy, but also fundamental information about potential mechanisms of action.